The aggregation and precipitation of proteins are implicated in the origins of various neurodegenerative disorders such as Alzheimer's, Parkinson's and St. Vitus' dance (“Huntington's Chorea”). In Alzheimer's disease the amyloid-β-peptide (Aβ) aggregates and leads to insoluble senile plaques which constitute one of the pathological markers of the disease. Aβ is formed by the proteolytic cleaving of a precursor protein, amyloid precursor protein (APP). Two methods of metabolising APP have been detected, the non-amyloidogenic method and the amyloidogenic method.
In the non-amyloidogenic metabolism of APP, α-secretase cleaves within the Aβ region of the APP and thus leads to the secretion of the soluble N-terminal region of the protein (α-APPs) and, after the γ-secretase cutting has taken place, to the release of p3. By contrast, the amyloidogenic route leads to the formation of Aβ, two proteases generating the N-terminus (β-secretase) and the C-terminus (γ-secretase), respectively, of Aβ.
Aβ can be detected in human plasma and cerebrospinal fluid in vivo. In cell culture, too, secreted Aβ can be detected in the cell culture supernatant of various types of cells which express or overexpress APP or fragments thereof endogenously.
The problem of the present invention is to prepare compounds which are capable of interfering (preferably in an inhibitory capacity) in the process of the formation of Aβ or its release from cells, or of reducing the activity of Aβ by inhibiting it. Finally, the present invention is based on the further objective of preparing compounds which can be used effectively for the prevention or treatment of Alzheimer's disease.